This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1a, MIP-1b, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1a, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1a, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1a, RANTES, MIP-1b] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d) [I-309, TARC, MIP-1b] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: 
wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR8CONHR9, and R8 and R9 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such Spiro compounds are not considered part of the present invention.
U.S. Pat. No. 5,264,420 discloses fibrinogen receptor antagonists comprising carbon-linked disubstituted heterocyclic amines as a component of a multiamidic moiety: 
These compounds can be distinguished from the present invention by the nature of the multiamidic moiety.
WO 96/31111 discloses farnesyl protein transferase inhibitors where R2 can be C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR8COR9 and xe2x80x94NR8CONR9R10 wherein R9 may be phenyl which can have further substitution. 
Such compounds which contain tri-substituted ketones are not contemplated by the present invention.
WO 96/11200 discloses purine and guanine compounds as inhibitors of purine nucleoside phosphorylase: 
wherein R4 can be C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NHCONHAr where Ar may be phenyl further substituted. Such guanines and purines as substituents on heterocycles are not considered part of the present invention.
Compounds known in the art are readily distinguished structurally by either the nature or location of the linking chain, or other possible substitution patterns of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel heterocycles as having activity toward the chemokine receptors.
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein J, K, L, M, R1, R2, R3, and R4 are defined below are effective modulators of chemokine activity.
Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
J is selected from CH2 and CHR5;
K and L are independently selected from CR5R6 and CR6R6;
M, at each occurrence, is selected from CR5R6 and CR6R6;
with the proviso that at least one of J, K, L, or M contains an R5;
X is selected from (CR7xe2x80x2R7xe2x80x2)qxe2x80x94Sxe2x80x94(CR7xe2x80x2R7xe2x80x2)q, (CR7xe2x80x2R7xe2x80x2)qxe2x80x94Oxe2x80x94(CR7xe2x80x2R7xe2x80x2)q, (CR7xe2x80x2R7xe2x80x2)qxe2x80x94NR7xe2x80x94(CR7xe2x80x2R7xe2x80x2)q, (CR7xe2x80x2R7xe2x80x2)rxe2x80x94C(O)xe2x80x94(CR7xe2x80x2R7xe2x80x2)q, C1-6 alkylene substituted with 0-5 R7, C2-10 alkenylene substituted with 0-5 R7, C2-10 alkynylene substituted with 0-5 R7, and (CR7R7)txe2x80x94Axe2x80x94(CR7R7)t substituted with 0-3 R8;
with the proviso that when R7 or R7xe2x80x2 is bonded to the same carbon as Y, R7 is not halogen, cyano, or bonded through a heteroatom;
A is C3-6 carbocyclic residue;
Y is selected from NR11C(xe2x95x90O)NR11, NR11C(xe2x95x90S)NR11, NR11C(xe2x95x90NRa)NR11, NR11C(xe2x95x90CHCN)NR11, NR11C(xe2x95x90CHNO2)NR11, NR11C(xe2x95x90C(CN)2)NR11, NR11, C(O), S(O)2NR11, NR11S(O)2, NR11S(O)2NR11, C(O)NR11, NR11C(O), NR11C(O)O, OC(O)NR11, and S(O)p;
Ra is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, Oxe2x80x94C1-6 alkyl, and (CH2)wphenyl;
R1 is selected from a (CR1xe2x80x2R1xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9 and a (CR1xe2x80x2R1xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9;
R1xe2x80x2 and R1xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R2, at each occurrence, is selected from H, C1-8 alkyl, (CR2xe2x80x2R2xe2x80x3)qNR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)wOH, (CR2xe2x80x2R2xe2x80x3)wO(CR2xe2x80x2R2xe2x80x3)rR12d, (CR2xe2x80x2R2xe2x80x3)qSH, (CR2xe2x80x2R2xe2x80x3)rC(O)H, (CR2xe2x80x2R2xe2x80x3)qS(CR2xe2x80x2R2xe2x80x3)rR12d, (CR2xe2x80x2R2xe2x80x3)rC(O)OH, (CR2xe2x80x2R2xe2x80x3)rC(O)(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wNR12aC(NRa)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(NRa)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(NRa)R12b, (CR2xe2x80x2R2xe2x80x3)rC(O)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fC(O)(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)rC(O)O(CR2xe2x80x2R2xe2x80x3)rR12d, (CR2xe2x80x2R2xe2x80x3)wOC(O)(CR2xe2x80x2R2xe2x80x2)rR12b, (CR2xe2x80x2R2xe2x80x3)wS(O)p(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wS(O)2NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fS(O)2(CR2xe2x80x2R2xe2x80x3)rR12b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R12c, C2-8 alkynyl substituted with 0-3 R12c, a (CR2xe2x80x2R2xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R12c, and a (CH2)rxe2x80x945-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R12c;
alternatively, R2 is an amino acid residue;
R2xe2x80x2 and R2xe2x80x3, at each occurrence, are selected from H, C2-8 alkenyl, C2-8 alkynyl, (CF2)rCF3, (CH2)rCN, (CH2)rNO2, (CF2)rCF3, (CH2)rNR2aR2a, (CH2)rOH, (CH2)rOR2b, (CH2)rSH, (CH2)rSR2b, (CH2)rC(O)OH, (CH2)rC(O)R2b, (CH2)rC(O)NR2aR2axe2x80x2, (CH2)rNR2dC(O)R2a, (CH2)rC(O)OR2b, (CH2)rOC(O)R2b, (CH2)rS(O)pR2b, (CH2)rS(O)2NR2aR2axe2x80x2, (CH2)NR2dS(O)2R2b, C1-6 haloalkyl, a (CR2xe2x80x2R2xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R2c, and a (CH2)rxe2x80x945-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R2c;
R2a and R2axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R2c;
R2b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R2c;
R2c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR2dR2d, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R2b, (CH2)rC(O)NR2dR2d, (CH2)rNR2dC(O)R7a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R2b, (CH2)rC(xe2x95x90NR2d)NR2dR2d, (CH2)rS(O)pR2d, (CH2)rNHC(xe2x95x90NR2d)NR2dR2d, (CH2)rS(O)2NR2dR2d, (CH2)rNR2dS(O)2R2b, and (CH2)rphenyl substituted with 0-3 R9e;
R2d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R3 is selected from HF C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)rCF3, (CH2)qNR3aR3axe2x80x2, (CH2)qOH, (CH2)qOR3b, (CH2)qSH, (CH2)qSR3b, (CH2)rC(O)OH, (CH2)rC(O)R3b, (CH2)rC(O)NR3aR3axe2x80x2, (CH2)qNR3dC(O)R3a, (CH2)rC(O)OR3b, (CH2)qOC(O)R3b, (CH2)rS(O)pR3b, (CH2)rS(O)2 NR3aR3axe2x80x2, (CH2)qNR3dS(O)2R3b, and (CH2)r-phenyl substituted with 0-3 R3c;
R3a and R3axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R3c;
R3b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R3c;
R3c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR3dR3d;
R3d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4axe2x80x2, (CH2)qC(O)OR4b, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4c;
R4a and R4axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
R5 is selected from a (CR5xe2x80x2R5xe2x80x3)txe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10 and a (CR5xe2x80x2R5xe2x80x3)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10;
R5xe2x80x2 and R5xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
alternatively, R5 and R6 join to form a 5, 6, or 7-membered spirocycle, containing 0-3 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R6, at each occurrence, is selected from H, C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6axe2x80x2, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2NR6aR6axe2x80x2, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, (CH2)rOH, (CH2)rSH, (CH2)rOR7d, (CH2)rSR7d, (CH2)rNR7aR7axe2x80x2, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R7c;
R7a and R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 cycloalkyl, and phenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-6 alkyl, OH, SH, (CH2)rSC1-6 alkyl, (CH2)rNR7dR7d, C(O)C1-6 alkyl, and (CH2)rphenyl;
R7d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R7xe2x80x2, at each occurrence, is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR7b, (CH2)qSR7b, (CH2)qNR7aR7axe2x80x2, (CH2)rC(O)OH, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R7c;
R8, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR8aR8axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR8d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR8d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR8b, (CHRxe2x80x2)rC(O)NR8aR8axe2x80x2, (CHRxe2x80x2)rNR8fC(O)(CHRxe2x80x2)rR8b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR8d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR8b, (CHRxe2x80x2)rC(xe2x95x90NNR8f)NR8aR8axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR8f)NR8fR8f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR8b, (CHRxe2x80x2)rS(O)2NR8aR8axe2x80x2, (CHRxe2x80x2)rNR8fS(O)2(CHRxe2x80x2)rR8b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R8e;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R8e;
R8a and R8axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R8e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R8e;
R8b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R8e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R8e;
R8d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R8e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R8e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R8e;
R8e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br; I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR8fR8f, and (CH2)rphenyl;
R8f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R9, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR9aR9axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR9d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR9d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rC(O)NR9aR9axe2x80x2, (CHRxe2x80x2)rNR9fC(O)(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR9d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rC(xe2x95x90NR9f)NR9aR9axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR9f)NR9fR9f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rS(O)2NR9aR9axe2x80x2, (CHRxe2x80x2)rNR9fS(O)2(CHRxe2x80x2)rR9b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R9e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R9e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R9e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R10, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR10aR10axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR10d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR10d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR10b, (CHRxe2x80x2)rC(O)NR10aR10axe2x80x2, (CHRxe2x80x2)rNR10fC(O)(CHRxe2x80x2)rR10b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR10d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR10b, (CHRxe2x80x2)rC(xe2x95x90NR10f)NR10aR10axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR10f)NR10fR10f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR10b, (CHRxe2x80x2)rS(O)2NR10aR10axe2x80x2, (CHRxe2x80x2)rNR10fS(O)2(CHRxe2x80x2)rR10b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R10e;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R10e;
R10b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R10e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R10e;
R10d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R10e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R10e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
R10f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R11, at each occurrence is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11a;
R11a, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11bR11b, (CH2)rOH, (CH2)rOR11c, (CH2)rSH, (CH2)rSR11c, (CH2)rC(O)R11b, (CH2)rC(O)NR11bR11b, (CH2)rNR11bC(O)R11b, (CH2)rC(O)OR11b, (CH2)rOC(O)R11c, (CH2)rCH(xe2x95x90NR11b)NR11bR11b, (CH2)rNHC(xe2x95x90NR11b)NR11bR11b, (CH2)rS(O)pR11c, (CH2)rS(O)2NR11bR11b, (CH2)rNR11bS(O)2R11c, and (CH2)rphenyl;
R11b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R11c, at each occurrence, is selected from C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R12a and R12axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl substituted with 0-3 R12e, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R12e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R12e;
R12b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R12e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R12e;
R12c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR12fR12f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R12b, (CH2)rC(O)NR12fR12f, (CH2)rNR12fC(O)R12a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R12b, (CH2)rC(xe2x95x90NR12f)NR12fR12f, (CH2)rS(O)pR12b, (CH2)rNHC(xe2x95x90NR12f)NR12fR12f, (CH2)rS(O)2NR12fR12f, (CH2)rNR12fS(O)2R12b, and (CH2)rphenyl substituted with 0-3 R12e;
R12d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R12e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R12e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR12fR12f, and (CH2)rphenyl;
R12f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
w is selected from 2, 3, 4, and 5;
v is selected from 0, 1 and 2;
t is selected from 0, 1 and 2;
r is selected from 0, 1, 2, 3, 4, and 5,
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 1, 2, and 3.
In certain embodiments, the present invention provides compound novel compounds of formula I, wherein:
R3 is selected from H, C1-6 alkyl, C2-8 alkenyl, and C2-8 alkynyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, CF3, (CH2)rOC1-5 alkyl, (CH2)rOH;
R6, at each occurrence, is selected from H, C1-4 alkyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, (CH2)rOH, (CH2)rOR6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
q is selected from 1, 2, and 3;
r is selected from 0, 1, 2, and 3; and
v is selected from 0, and 1.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R2, at each occurrence, is selected from H, C1-8 alkyl, (CH2)rC(O)R12b, (CH2)rC(O)NR12aR12axe2x80x2, (CH2)rC(O)OR12d, (CH2)rS(O)pR12b, (CH2)rS(O)2NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)wNR12sC(NRa) NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(NRa)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(NRa)R12b, a (CH2)r-carbocyclic residue substituted with 0-3 R12c, wherein the carbocyclic residue is selected from:
phenyl, C3-6 cycloalkyl, napthyl, and adamantyl; and a (CH2)r-5-6 membered heterocyclic system substituted with 0-2 R12c, wherein the heterocyclic system is selected from:
pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;
alternatively, R2 is an amino acid residue;
R7, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, (CH2)rOH, (CH2)rOR7d, (CH2)rNR7aR7axe2x80x2, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7a and R7a, at each occurrence, are selected from H, C1-6 alkyl;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7e is selected from H and C1-6 alkyl;
R7xe2x80x2 is H;
R11, at each occurrence is selected from H, and C1-8 alkyl;
R12a and R12axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, and phenyl with 0-3 R12e;
R12b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R12e;
R12c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR12fR12f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rC(O)R12b, (CH2)rC(O)NR12fR12f, (CH2)rNR12fC(O)R12a, (CH2)rS(O)2NR12fR12f, (CH2)rNR12fS(O)2R12b, and (CH2)rphenyl substituted with 0-3 R12e;
R12e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)rNR12fR12f, and (CH2)rphenyl; and
R12f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl.
In certain embodiments, the present invention provides compounds of formula I, wherein:
A is selected from phenyl, cyclohexyl, cyclopentyl, and cyclopropyl;
R1 is selected from a (CR1xe2x80x2H)r-carbocyclic residue substituted with 0-5 R9, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, napthyl, and adamantyl; and a (CR1xe2x80x2H)r-heterocyclic system substituted with 0-3 R9, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R10; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R10, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In certain embodiments, the present invention provides compounds of formula I, wherein:
X is selected from C1-5 alkylene substituted with 0-5 R7, C2-10, C2-6 alkynylene substituted with 0-5 R7, and (CR7R7)txe2x80x94Axe2x80x94(CR7R7)t substituted with 0-4 R8; and
Y is selected from NHC(xe2x95x90O)NH, NHC(xe2x95x90S)NH, NHC(xe2x95x90NRa)NH, NHC(xe2x95x90CHCN)NH, NHC(xe2x95x90CHNO2)NH, NHC(xe2x95x90C(CN)2)NH, C(O)NH, and NHC(O).
In certain embodiments, the present invention provides compounds of formula I-i: 
wherein:
R8, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR8aR8axe2x80x2, NO2, CN, OH, (CH2)rOR8d, (CH2)rC(O)R8b, (CH2)rC(O)NR8aR8axe2x80x2, (CH2)rNR8fC(O)R8b, (CH2)rS(O)pR8b, (CH2)rS(O)2NR8aR8axe2x80x2, (CH2)rNR8fS(O)2R8b, and (CH2)rphenyl substituted with 0-3 R8e;
R8a and R8axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R8e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R8f, at each occurrence, is selected from H, and C1-5 alkyl.
R10, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR10aR10axe2x80x2, NO2, CN, OH, (CH2)rOR10d, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10axe2x80x2, (CH2)rNR10fC(O)R10b, (CH2)rS(O)pR10b, (CH2)rS(O)2NR10aR10axe2x80x2, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R10e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R10f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain embodiments of formula I-i, the present invention provides novel compounds, wherein:
R5 is CH2phenyl substituted with 0-3 R10;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
M is selected from CH2 and CHR5;
R9, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR9aR9axe2x80x2, NO2, CN, OH, (CH2)rOR9d, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9fC(O)R9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9fS(O)2R9b, (CH2)rphenyl substituted with 0-3 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R9f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain embodiments of formula I-i, the present invention provides novel compounds, wherein:
X is C1-4 alkylene selected from methylene, ethylene, propylene, and butylene; wherein C1-4 alkylene is substituted with 0-2 R7;
R7, at each occurrence, is selected from C1-3 alkyl, (CH2)rOH, (CH2)rOR7d, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)rNR7fR7f;
R7f is selected from H and C1-6 alkyl; and
Y is selected from NHC(xe2x95x90O)NH, NHC(xe2x95x90NRa)NH, NHC(xe2x95x90CHCN)NH, C(O)NH, and NHC(O).
In certain embodiments, the present invention provides novel compounds of formula I-ii: 
wherein:
R8, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR8aR8axe2x80x2, NO2, CN, OH, (CH2)rOR8d, (CH2)rC(O)R8b, (CH2)rC(O)NR8aR8axe2x80x2, (CH2)rNR8fC(O)R8b, (CH2)rS(O)pR8b, (CH2)rS(O)2NR8aR8axe2x80x2, (CH2)rNR8fS(O)2R8b, and (CH2)rphenyl substituted with 0-3 R8e;
R8a and R8axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R8e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R8f, at each occurrence, is selected from H, and C1-5 alkyl.
R10, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR10aR10axe2x80x2, NO2, CN, OH, (CH2)rOR10d, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10axe2x80x2, R10fC(O)R10b, (CH2)rS(O)pR10b, (CH2)rS(O)2NR10aR10axe2x80x2, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R10e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R10f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain embodiments of formula I-ii, the present invention provides novel compounds, wherein:
R5 is CH2phenyl substituted with 0-3 R10;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R9, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR9aR9axe2x80x2, NO2, CN, OH, (CH2)rOR9d, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9fC(O)R9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9fS(O)2R9b, (CH2)rphenyl substituted with 0-3 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R9f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain embodiments of formula I-ii, the present invention provides novel compounds, wherein:
X is C1-4 alkylene selected from methylene, ethylene, propylene, and butylene; wherein C1-4 alkylene is substituted with 0-2 R7;
R7, at each occurrence, is selected from C1-3 alkyl, (CH2)rOH, (CH2)rOR7d, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)rNR7fR7f;
R7f is selected from H and C1-6 alkyl; and
Y is selected from NHC(xe2x95x90O)NH, NHC(xe2x95x90NRa)NH, NHC(xe2x95x90CHCN)NH, C(O)NH, and NHC(O).
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
when v is 0, L is CH2;
when v is 1, M is CH2; or
when v is 2, the M adjacent to the carbon bearing R3 is CH2.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
A is selected from phenyl, cyclohexyl, cyclopentyl, and cyclopropyl;
R7, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, (CH2)rOH, (CH2)rOR7d, (CH2)rNR7aR7axe2x80x2, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7a and R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7e is selected from H and C1-6 alkyl;
R7xe2x80x2 is H;
R8, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR8aR8axe2x80x2, NO2, CN, OH, (CH2)rOR8d, (CH2)rC(O)R8b, (CH2)rC(O)NR8aR8axe2x80x2, (CH2)rNR8fC(O)R8b, (CH2)rS(O)pR8b, (CH2)rS(O)2NR8aR8axe2x80x2, (CH2)rNR8fS(O)2R8b, and (CH2)rphenyl substituted with 0-3 R8e;
R8a and R8axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R8e;
R8d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R8e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R8f, at each occurrence, is selected from H and C1-5 alkyl; and
R11, at each occurrence, is selected from H, and C1-8 alkyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R1 is selected from a carbocyclic residue substituted with 0-3 R9, wherein the carbocyclic residue is selected from phenyl and C3-6 cycloalkyl; and a heterocyclic system substituted with 0-3 R9, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-3 R10; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R10, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein v is 1, M is CH2, and J is CH2.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R3 is H and R4 is absent.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R9, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR9aR9axe2x80x2, NO2, CN, OH, (CH2)rOR9d, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9fC(O)R9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9fS(O)2R9b, (CH2)rphenyl substituted with 0-3 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R9f, at each occurrence, is selected from H, and C1-5 alkyl;
R10, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR10aR10axe2x80x2, NO2, CN, OH, (CH2)rOR10d, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10axe2x80x2, (CH2)rNR10fC(O)R10b, (CH2)rS(O)pR10b, (CH2)rS(O)2NR10aR10axe2x80x2, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R10e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R10f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain preferred embodiments, the present invention provides novel compounds of formula I, wherein K is CH2, L is CHR5, wherein R5 is substituted with 0-3 R10.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R5 is a benzyl group (CH2-phenyl) substituted with 0-3 R10.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R1 is phenyl substituted with 0-3 R9.
In certain embodiments, the present invention provides novel compounds of formula I, wherein X is propylene substituted with 0-3 R7.
In a certain embodiments, the present invention provides novel compounds of formula I, wherein:
R7, at each occurrence, is selected from C1-3 alkyl, (CH2)rOH, (CH2)rOR7d, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)rNR7fR7f; and
R7f is selected from H and C1-6 alkyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R2, at each occurrence, is selected from H, C1-8 alkyl, (CR2xe2x80x2R2xe2x80x3)qNR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)wOH, (CR2xe2x80x2R2xe2x80x3)wO(CR2xe2x80x2R2xe2x80x3)rR12d, (CR2xe2x80x2R2xe2x80x3)rC(O)(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wNR12aC(NRa)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(O)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fC(O)(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wS(O)2NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fS(O)2(CR2xe2x80x2R2xe2x80x3)rR12b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 R12c, C2-8 alkynyl substituted with 0-3 R12c, a (CR2xe2x80x2R2xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R12c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R12c;
alternatively, R2 is an amino acid residue; and
R2xe2x80x2 and R2xe2x80x3, at each occurrence, are selected from H, C1-8 alkyl, C2-8 alkenyl, (CH2)rOH, (CH2)rOR2b, (CH2)rC(O)R2b, (CH2)rC(O)NR2aR2axe2x80x2, (CH2)rNR2dC(O)R2a.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R2, at each occurrence, is selected from H, C1-8 alkyl, (CH2)qNR12aR12axe2x80x2, (CH2)wOH, (CH)wO(CR2xe2x80x2R2xe2x80x3)rR12d, (CR2xe2x80x2R2xe2x80x3)rC(O)(CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wNR12aC(NRa)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)rC(O)NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fC(O) (CR2xe2x80x2R2xe2x80x3)rR12b, (CR2xe2x80x2R2xe2x80x3)wS(O)2NR12aR12axe2x80x2, (CR2xe2x80x2R2xe2x80x3)qNR12fS(O)2(CR2xe2x80x2R2xe2x80x3)rR12b;
R2xe2x80x2 and R2xe2x80x3 are H;
r is selected from 0, 1, and 2; and
w and q are selected from 2 and 3.
In certain embodiments, the present invention provides novel compounds of formula I, wherein X is unsubstituted propylene.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R5 is substituted with 0-2 R10.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R10, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, C(O)C1-4 alkyl, (CH2)rNR10aR10axe2x80x3, CN, OH, OCF3, (CH2)rOR10d;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, and C3-6 cycloalkyl; and
R10d is C1-6 alkyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R10 is selected from F, Cl, Br, OCF3, and CF3.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R1 is substituted with 0-2 R9.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
R9, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, F, NO2, CN, (CHRxe2x80x2)rNR9aR9axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR9d, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rC(O)NR9aR9axe2x80x2, (CHRxe2x80x2)rNR9fC(O)(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR9d, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR9b, (CHRxe2x80x2)rS(O)2NR9aR9axe2x80x2, (CHRxe2x80x2)rNR9fS(O)2(CHRxe2x80x2)rR9b, CF3, OCF3, (CHRxe2x80x2)rphenyl substituted with 0-3 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R9e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e;
R9d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R9e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R9e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl; and
R9f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R1 is phenyl substituted with R9 groups which occupy the 3, or the 5, or both the 3 and 5 positions on the phenyl ring.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R9, at each occurrence, is selected from C(O)R9b, C(O)ORd, C(O)OH, CN, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e.
In certain embodiments, the present invention provides novel compounds of formula I, wherein Y is selected from NR11C(xe2x95x90S) NR11, NR11C(xe2x95x90NRa) NR11, NR11C(xe2x95x90CHCN)NR11, NR11C(xe2x95x90CHNO2)NR11, NR11C(xe2x95x90C(CN)2)NR11, NR11, C(O), S(O)2NR11, NR11S(O)2, NR11S(O)2NR11, C(O)NR11, NR11C(O), NR11C(O)O, OC(O)NR11, and S(O)p.
In certain embodiments, the present invention provides novel compounds of formula I, wherein Y is selected from NR11C(xe2x95x90NRa)NR11, NR11C(xe2x95x90CHCN)NR11, NR1C(xe2x95x90CHNO2)NR11, and NR11C(xe2x95x90C(CN)2)NR11.
In certain embodiments, the present invention provides novel compounds of formula I, wherein Y is NR11C(xe2x95x90NCN)NR11.
In certain embodiments, the present invention provides novel compounds of formula I, wherein Y is NR11C(xe2x95x90C(CN)2)NR11.
In certain embodiments, the present invention provides novel compounds of formula I, wherein Y is selected from NR11C(xe2x95x90C(CN)2)NR11 and NR11C(xe2x95x90NCN)NR11, and R11, at each occurrence, is selected from H and C1-6 alkyl.
In certain embodiments, the present invention provides novel compounds of formula I, wherein R9, at each occurrence, is selected from C(O)R9b, C(O)ORd, C(O)OH, CN, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R9e.
In certain embodiments, the present invention provides novel compounds of formula I, wherein:
X is (CR7R7)txe2x80x94Axe2x80x94(CR7R7)t substituted with 0-3 R8;
R7, at each occurrence, is selected from C1-3 alkyl, (CH2)rOH, (CH2)rOR7d, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)rNR7fR7f;
R7f is selected from H and C1-6 alkyl;
R8, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR8fR8f, NO2, CN, OH, (CH2)rOR8d, and (CH2)rphenyl substituted with 0-3 R8e;
R8d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R8e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R8f, at each occurrence, is selected from H and C1-5 alkyl.
In certain preferred embodiments, the present invention provides novel compounds of formula I, wherein the compound of formula I is selected from:
(+)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(4-phenylmethyl)-1-methyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(4-phenylmethyl)-1-acetyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmnethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl)methyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-N-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-Nxe2x80x2-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-Nxe2x80x2-[4-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-([2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[2-(5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[2-5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carboethoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-chlorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-phenyl-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-cyano-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-acetyl-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-fluoro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-fluoro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-chloro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(4-chloro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-trans-N-(3-methoxy-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-Nxe2x80x2-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-Nxe2x80x2-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carbomethoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carboethoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-fluorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-fluorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-chlorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-chlorophenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-methoxyphenyl)-Nxe2x80x2-[5-(phenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-phenyl-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-cyano-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-acetyl-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carbomethoxy-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-carboethoxy-phenyl)-Nxe2x80x2-[5-(4- fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-fluoro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-fluoro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(3-chloro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,
(xc2x1)-cis-N-(4-chloro-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea, and
(xc2x1)-cis-N-(3-methoxy-phenyl)-Nxe2x80x2-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea.
In other preferred embodiments, the present invention provides novel compounds of formula I, wherein the compound of formula I is selected from:
(xc2x1)-cis-N-{3-[4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(3-cyanophenyl)urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[2-[4-(benzyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-3-cyanobenzamide,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[2-[4-(benzyl)-2-piperidinyl]ethyl urea,
(xc2x1)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-4-fluorobenzenesulfonamide,
(xc2x1)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}benzamide,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-chlorophenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(phenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-fluorophenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-methoxyphenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-carboethoxyhenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(4-fluorophenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-trifluoromethylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-cyanophenyl)-Nxe2x80x2-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propyl urea,
(xc2x1)-cis-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-cyanophenyl)-Nxe2x80x2-[4-[4-(benzyl)-2-piperidinyl]butyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[4-[4-(benzyl)-2-piperidinyl]butyl urea,
N-(3-acetylphenyl)-Nxe2x80x2-{[3-[2S,4S]-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{[4-[2R,4R]-4-(4-fluorobenzyl)-2-piperidinyl]butyl}urea,
N-(3-cyanophenyl)-Nxe2x80x2-{[4-[2R,4R]-4-(4-fluorobenzyl)piperidinyl]butyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(2,4-difluorobenzyl)piperidinyl]propyl}urea,
N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-(3,5-diacetylphenyl)urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,
N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-(3,5-diacetylphenyl)urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-1-(2-hydroxyethyl)-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-1-methyl-2-piperidinyl]propyl urea,
(xc2x1)-trans-N-(3-acetylphenyl)-Nxe2x80x2-[3-[4-(benzyl)-1-ethyl-2-piperidinyl]propyl urea,
N-(3-acetylphenyl)-Nxe2x80x2-{-[3-(2R,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{-[3-(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-methylpiperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,
[(2S,4R)-2-(3-{-[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]acetic acid,
N-(3-acetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-1-benzyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
(xc2x1)-trans-N-{3-[(4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(3-fluoro-4-methylphenyl)urea,
(xc2x1)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(3,4-dimethoxyphenyl)urea,
(xc2x1)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(6-methoxy-3-pyridinyl)urea,
(xc2x1)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(1H-indazol-6-yl)urea,
N-(3-acetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-1-(cyclopropylmethyl)-4-(4-fluorobenzyl)piperidinyl]propyl)urea,
N-(3-cyanophenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3-cyanophenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,
N-(3-acetylphenyl)-Nxe2x80x2-(3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,
N-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}-Nxe2x80x2-(3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,
(2S,4R)-2-(3-{[(E)-{[(E)-amino(oxo)methyl]imino}(3,5-diacetylanilino)methyl]amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,
N-[(E)-({3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}amino)(3,5-diacetylanilino)methylidene]urea,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}guanidine,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,
N-[(E)-(3,5-diacetylanilino)({3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,
(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}guanidine,
(2S,4S)-2-(3-{[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,
N-{3-[(2S,4R)-1-(aminoacetyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-(3,5-diacetylphenyl)urea,
N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x3-cyano-Nxe2x80x2-(3,5-diacetylphenyl)guanidine,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}guanidine,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}guanidine,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-methylpiperidinyl]propyl}guanidine,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-1-ethyl-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,
N-[3,5-bis(1-methyl-1H-tetraazol-5-yl)phenyl]-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-[3,5-bis(1-methyl-1H-tetraazol-5-yl)phenyl]urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-1-(2,2-difluoroethyl)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(methylsulfonyl)piperidinyl]propyl}urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propionylpiperidinyl]propyl}urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-isobutyrylpiperidinyl]propyl}urea,
(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,
(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboxamide,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-pyridinylmethyl)piperidinyl]propyl}urea,
2-[(2S,4R)-2-(3-{-[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]acetamide,
N-{3-[(2S,4R)-1-[(2S)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-(3,5-diacetylphenyl)urea,
N-{3-[(2S,4R)-1-[(2R)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-Nxe2x80x2-(3,5-diacetylphenyl)urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}urea,
1-(3-{[(E)-1-({3-[(2S)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)-2-nitroethenyl]amino}phenyl)ethanone,
(xc2x1)-trans-N-{3-[4-(benzyl)-2-piperidinyl]propyl}-Nxe2x80x2-[3-(phenylsulfonyl)phenyl]urea,
(xc2x1)-trans-N-{3-[4-(benzyl)-2-piperidinyl]propyl}-Nxe2x80x2-[3-chloro-4-(diethylamino)phenyl]urea,
(xc2x1)-trans-N-(3-{[({3-[4-benzyl-2-piperidinyl)propyl}amino)carbonyl]amino}phenyl)acetamide,
(xc2x1)-trans-N-{3-[4-benzylpiperidinyl]-2-propyl}-Nxe2x80x2-[3-(1-hydroxyethyl)phenyl]urea,
(xc2x1)-trans-dimethyl 5-{[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}isophthalate,
(xc2x1)-trans-ethyl 3-{-[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}benzoate,
(xc2x1)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-Nxe2x80x2-(3-chlorophenyl)urea,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}urea,
N-[3-(2-{3-[(3,5-diacetylanilinocarbonyl)amino}propyl}-4-(4-fluorobenzyl)-1-piperidinyl)propyl]acetamide,
N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}urea,
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}guanidine, and
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}guanidine.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention
In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin""s disease, and colonic carcinoma.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)).
The compounds of Formula I can also be quaternized by standard techniques such as alkylation of the piperidine or pyrrolidine with an alkyl halide to yield quaternary piperidinium salt products of Formula I. Such quaternary piperidinium salts would include a counterion. As used herein, xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, the term xe2x80x9cpiperidinium spirocycle or pyrrolidinium spirocyclexe2x80x9d is intented to mean a stable spirocycle ring system, in which the two rings form a quarternary nitrogene at the ring junction.
As used herein, the term xe2x80x9c5-6-membered cyclic ketalxe2x80x9d is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 10-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9camino acidxe2x80x9d or xe2x80x9camino acid residuexe2x80x9d is intended to have its art-recognized meaning as a molecule containing both an amino group and a carboxyl group separated by a carbon. Embodiments of amino acids include xcex1-amino acids; i.e., carboxylic acids of general formula HOOC-CH(NH2)xe2x80x94(side chain). Side chains of amino acids include naturally occurring and non-naturally occurring moieties. Non-naturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75, the disclosure of which is hereby incorporated by reference. In certain embodiments, substituent groups for the compounds include the residue of an amino acid after removal of the hydroxyl moiety of the carboxyl group thereof; i.e., groups of Formula xe2x80x94C(xe2x95x90O) CH(side chain) (N(G)2)xe2x80x94, wherein G is a group including, but not limited to, hydrogen, a nitrogen protecting group, or another amino acid.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The following abbreviations are used herein: xe2x80x9cTHFxe2x80x9d as used herein is intended to mean tetrahydrofuran, xe2x80x9cEtOAcxe2x80x9d as used herein is intended to mean ethyl acetate, xe2x80x9cDMAPxe2x80x9d as used herein is intended to mean 4-N,N-dimethylamino pyridine, xe2x80x9c9-BBNxe2x80x9d as used herein is intended to mean 9-borabicyclo [3.3.1]nonane, xe2x80x9cBoc2Oxe2x80x9d as used herein is intended to mean Di-tert-Butyl dicarbonate, xe2x80x9cNMOxe2x80x9d as used herein intended to mean N-methyl morpholine-N-oxide, xe2x80x9cTPAPxe2x80x9d as used herein is intended to mean tetrapropylammonium perruthenate, xe2x80x9cTFAxe2x80x9d as used herein is intended to mean trifluoroacetic acid. The compounds of Formula I can be prepared using the reactions and techniques described below. 
The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. 
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
Compounds of the Formula Ia-d are prepared by alkylating heterocycles IIa-d by using the appropriate conditions according to Scheme 1. Thus, heterocycles Ia-d can be alkylated with an alkyl sulfonate or alkyl halide according to the general methods described for this transformation in March, J. xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d 4th Ed., John Wiley and Sons, New York, 1992, pp. 411-413 (Herein after March, 4th Ed) Heterocycles IIa-d can also be treated with an aldehyde and an appropriate reducing agent to give Ia-d as described in March, 4th Ed. (pp. 898-900.)
The required aldehydes can be prepared by methods generally known to those skilled in the art of organic synthesis. Furthermore, heterocycles IIa-d can be acylated and the resulting amides reduced by the appropriate reducing agent to give Ia-d using procedures described in March, 4th Ed. (pp. 419-421 and 1212-1213, respectively.) Heterocycle IIa can be prepared by the following sequence outlined in Scheme 2. Imide III can be alkylated with an alkyl sulfonate, triflate or halide according to the methods described in the literature, more specifically, but not limited to, as described by Dieter, R. K. et al., Journal of Organic Chemistry, 1996, Vol. 61, pp. 4180-4184 to give IV. Substituted imide IV can then be reduced to the xcex1-alkoxy or xcex1-hydroxy urethane V according to the methods described in the literature, more specifically, but not limited to, as described by Nagasaka, T. et. al, Heterocycles, Vol. 24, No. 5, 1986.
Ionization of urethane V with a Bronstead or Lewis Acid generates an electrophilic acyl iminium ion which can be treated with a variety of nucleophiles according to the general methods outlined by, but not limited to, Shono, T. Tetrahedron, Vol. 40. No. 5, pp. 811-850, 1984., to give heterocycle VI. The side chain functionality (X) of VI can then be further modified or functionalized, if necessary, and the nitrogen deprotected (removal of Q), both using methods known to those skilled in the art of organic synthesis to provide heterocycle IIa. 
By way of further illustration (Scheme 2a), when Xxe2x95x90xe2x80x94CH2CHxe2x95x90CH2 (allyl), manipulation by hydroboration, conversion to an alkyl or aryl sulfonate, displacement with azide and hydrogenation provides amine XXX. Reaction with the appropriate acylating reagent and removal of Q will provide heterocycles of the formula IIa. All of these simple transformations are known to those skilled in the art of organic synthesis. Furthermore, the preparation and use of several of the acylating reagents described in Scheme 2a is illustrated in P. Traxler, et al., J. Med. Chem. (1997), 40, 3601-3616 for reagent 1b and 1d; see K. S. Atwal, J. Med. Chem. (1998) 41, 271 for reagent 1c; and see also J. M. Hoffman, et al., J. Med. Chem. (1983) 26, 140-144). 
Heterocycle IIb can be prepared by the sequence outlined in Scheme 3. Unsaturated imide VIII can be prepared by the methods described in the literature, more specifically, but not limited to, as described by Comins, D., et al., Adv. Nitrogen Heterocycl., 1996, Vol. 2, pp. 251-294. Thus, pyridines of the formula VII can be converted to their pyridinium salts at low temperature, treated with an appropriate nucleophile and subsequently hydrolized to vinylogous imides of the formula VIII. This procedure can be conveniently performed to produce racemic material or be slightly modified to produce material of high enantiomeric excess. At this juncture, the urethane functionality (Q) can be modified, if warranted, to facilitate more convenient removal of Q at the end of the synthetic sequence. Imide VIII can be reduced according to methods known to those skilled in the art of organic synthesis to give ketone IX. Ketone IX can be converted to urethane X according to methods described in March, 4th Ed., pp. 956-963. The resulting urethane X can be processed in two separate manners. The side chain X can be manipulated prior to reduction of the olefin to give XI. Olefin XI and/or urethane X can then be reduced with reagents known to those skilled in the art of organic synthesis.
For example, by treatment with H2(g) accompanied by the appropriate catalyst (including, but not limited, to PtO2 or Pd on carbon) or by treatment with an alkaline earth metal such as lithium, sodium or calcium in the appropriate solvent mixture (ammonia mixed with THF or diethyl ether) to give XII or XIII, respectively. Heterocycle IIb can be prepared from XIII and/or XII with similar transformations described above for heterocycle VI. 
Imides similar to VIII (XIV) can also be converted into heterocycles of the formula IIc according to Scheme 4. Thus, treatment of XIV with strong base followed by alkylation of the resulting enolate with an appropriate electrophile generates unsaturated imide XV. Reaction of XV with an organometallic derivative according to, but not limited to, procedures described in March, 4th Ed., pp. 797-803 would provide ketone XVI. Reduction of ketone XVI using a variety of conditions described in, but not limited to, March, 4th Ed., pp. 1209-1211 would provide urethane XVII. Manipulation of XVII as previously described for VI and XII will yield heterocyles of the formula IIc. 
Imide VIII can also be used in the formation of compounds of the formula IId (Scheme 5). Thus, reaction of VIII with an organometallic reagent in an analogous fashion to the formation of XVI would provide XVIII. Reduction of the ketone XVIII using conditions described for ketone XVI would provide XIX. Conversion of XIX using the conditions previously described for VI, XII and XVII would give compounds of the formula IId. 
Heterocycles of the formula XII can also be prepared according to the procedure described in Scheme 6. Imide XXI can be prepared by the acylation of amide XX using the procedure described by, but not limited to, Hansen, M. M., et al., Tetrahedron Letters, Vol. 36. 1995, pp. 8949-8952. Imide XXI is then converted to unsaturated imide XXII by sulfenylation and oxidative elimination according to the procedures described in, but not limited to, Zoretic, P. A., et al., Journal of Organic Chemistry, Vol. 41, 1976, pp. 3587-89 and Torisawa, Y., et al., Journal of Organic Chemistry, Vol. 57, 1992, pp. 5741-5747, respectively . The R5 substituent can then be introduced using methods described in Scheme 4 for the conversion of XV to XVI. Imide XXIII can then be converted to heterocycle XII (via the intermediacy of XXIV) using the sequence described in Scheme 2 for the conversion of IV (via V) to VI.
Heterocycles of the formula VI, XII, XVII and XIX can also be prepared by the sequence described in Scheme 7. Aldehydes of the formula XXVa-d can be converted to acyl iminium ion precursors using the conditions described by, but not limited to, Speckamp, W. N. et al, in xe2x80x9cComprehensive Organic Synthesisxe2x80x9d B. M. Trost, Editor, Volume 2, pp. 1047-1082. The resulting protected lactamols of the formula XXVIa-d can also be prepared from amino acids of the formula XXVIIa-d. Cyclization of XXVIIa-d using conditions previously described for, but not limited to, IIa-d (Scheme 1, March, 4th. Ed. pp. 419-421) followed by partial reduction of the resulting imide (see the synthesis of V and XXIII, Scheme 2 and 6, respectively) and subsequent protection of the lactamol will provide XXVIa-d. 
The resulting lactamols (or their protected counterparts) can then be transformed into compounds of the formula VI, XII, XVII and XIX using conditions previously described for V (Scheme 2) or XXIV (Scheme 6). Acyclic precursors of the formula XXVa-d and XXVIIa-d can be prepared using methods know to those skilled in the art of organic synthesis.
Compounds of Formula XXIXa-d can be prepared by the method depicted in Scheme 8. The quaternary salts can be synthesized according to the methods described by, but not limited to, March, 4th Ed., pp. 411-413. The N-oxides of Formula XXIXa-d can be synthesized according to the methods described by, but not limited to, March, 4th Ed., pp. 1200-1201. 